Metastatic melanoma has rapidly increased in incidence throughout the world during the past decade. This insidious disease is generally undetected by many patients until reaching incurable stages. Since metastatic melanoma is currently considered to be incurable, research scientists have been encouraged to explore new avenues of cancer treatment which may provide hopeful perspectives in the handling of this invasive disease. Studies aimed at understanding the biological progression of this invasive process would undoubtedly be useful. The overall objective of our proposed research is to further explore, in a reliable in vitro model which we have developed, the study of human melanoma cell invasion that has been shown to correlate with an in vivo animal model; specifically, the heterogeneous invasive characteristics of high and low metastatic variants of melanoma cells as they interact with an extracellular basement membrane (human amnion) in the absence and presence of possible inhibitors and enhancers. The specific aims for this three-year project are: (1) to examine the intracellular and cell surface associated interactions of preinvasive, invasive and postinvasive melanoma tumor cells interacting with basement membranes in vitro; (2) to study the mechanism of tumor cell degradation by identifying the specific type(s) of plasminogen activator (PA) and/or proactivators and the physiological inhibitors of these activators produced by high and low metastatic variants in the invasion model; also, to measure the amount of PA activity associated with the cells when placed onto membranes; (3) to study the magnitude of the inhibitory or stimulatory effects of a specific biological response modifier, the exogenous addition of fibrinolytic components or antibodies to these components on melanoma tumor cells in vitro (particularly their degradative ability) as they interact with an extracellular barrier; and (4) to explore the nature of certain cell surface components that participate in tumor invasion. The latter will include the use of monoclonal antibodies to highly metastatic cell surface antigens (cell membrane glycoconjugates) of highly metastatic cells which could possibly modulate tumor cell invasion.